To date only four recombinant growth factors, including Filgrastim (rhG-CSF), have been approved by FDA as radiomitigators to ameliorate hematopoietic acute radiation syndrome (H-ARS). These approved agents are not stable under room-temperature, needing to be stored at 2–8 °C, and would not be feasible in a mass casualty scenario where rapid and cost-effective intervention is crucial. Delta-tocotrienol (δ-T3H), the most potent G–CSF–inducing agent among vitamin E isoforms, exhibited efficiency and selectivity on G-CSF production in comparison with TLR and STING agonists in mice. Five-dose δ-T3H was utilized as the optimal therapeutic regimen due to long-term G-CSF production and the best peripheral blood (PB) recovery of irradiated mice. Comparable with rhG-CSF, sequential administration of δ-T3H post-irradiation improved hematologic recovery and accelerated the regeneration of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in the bone marrow (BM) and spleen of 6.5Gy irradiated mice; and consistently enhanced repopulation of BM-HSCs. In 4.0Gy irradiated nonhuman primates, δ-T3H exhibited comparable efficacy as rhG-CSF to promote PB recovery and colony-formation of BM-HPCs. Altogether, we demonstrated that sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production, indicated δ-T3H as a promising radiomitigator for the management of H-ARS, particularly in a mass casualty scenario.

中文翻译：

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顺序施用 δ-生育三烯酚可通过诱导 G-CSF 产生改善小鼠和非人灵长类动物中辐射引起的骨髓抑制


迄今为止，只有四种重组生长因子，包括非格司亭 (rhG-CSF)，已被 FDA 批准作为缓解造血急性辐射综合征 (H-ARS) 的放射缓解剂。这些批准的药物在室温下不稳定，需要在 2-8°C 下储存，并且在大规模伤亡情况下不可行，而快速且具有成本效益的干预至关重要。 δ-生育三烯酚 (δ-T3H) 是维生素 E 亚型中最有效的 G-CSF 诱导剂，与 TLR 和 STING 激动剂相比，在小鼠体内表现出对 G-CSF 产生的效率和选择性。由于长期 G-CSF 产生和受辐射小鼠的最佳外周血 (PB) 恢复，五剂量 δ-T3H 被用作最佳治疗方案。与rhG-CSF相比，辐照后序贯给予δ-T3H可改善血液学恢复并加速6.5Gy辐照小鼠骨髓（BM）和脾脏中造血干细胞（HSC）和造血祖细胞（HPC）的再生;并持续增强 BM-HSC 的增殖。在 4.0Gy 照射的非人灵长类动物中，δ-T3H 在促进 PB 恢复和 BM-HPC 集落形成方面表现出与 rhG-CSF 相当的功效。总之，我们证明，连续施用 δ-生育三烯酚可通过诱导 G-CSF 产生来改善小鼠和非人类灵长类动物中辐射引起的骨髓抑制，表明 δ-T3H 作为治疗 H-ARS 的有前途的放射缓解剂，特别是在大规模治疗中伤亡场景。